Epidemiology of chronic kidney disease in children

In the past 30 years there have been major improvements in the care of children with chronic kidney disease (CKD). However, most of the available epidemiological data stem from end-stage renal disease (ESRD) registries and information on the earlier stages of pediatric CKD is still limited. The median reported incidence of renal replacement therapy (RRT) in children aged 0–19 years across the world in 2008 was 9 per million of the age-related population (4–18 years). The prevalence of RRT in 2008 ranged from 18 to 100 per million of the age-related population. Congenital disorders, including congenital anomalies of the kidney and urinary tract (CAKUT) and hereditary nephropathies, are responsible for about two thirds of all cases of CKD in developed countries, while acquired causes predominate in developing countries. Children with congenital disorders experience a slower progression of CKD than those with glomerulonephritis, resulting in a lower proportion of CAKUT in the ESRD population compared with less advanced stages of CKD. Most children with ESRD start on dialysis and then receive a transplant. While the survival rate of children with ERSD has improved, it remains about 30 times lower than that of healthy peers. Children now mainly die of cardiovascular causes and infection rather than from renal failure

Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study

Background: Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world. Methods: This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231. Findings: Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p < 0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05–2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p < 0·001). Interpretation: Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication

In vitro C3 mRNA expression is pemphigus vulgaris: Complement activation is increased by IL-1α and TNF-α

Background: Pemphigus vulgaris (PV) is a potentially life-threatening disease, characterized immunohistologically by IgG deposits and complement activation on the surface of keratinocytes. Complement activation has been implicated in the pathogenesis with C3 deposits in about 90% of patients. Objective: In order to further elucidate the role of complement in PV and to define which cytokines play a role in C3 mRNA expression, we performed an in vitro study in human keratinocytes. Methods: Normal human epidermal keratinocytes (NHuK) were incubated with PV serum and C3 mRNA was measured. We previously had shown that IL-1α and TNF-α. are expressed in PV in vivo and in vitro. Since cytokines are able to modulate complement activation, mRNA expression was evaluated in a similar experiment after pretreatment using antibodies against IL-1α and TNF-α. Results: Incubation of NHuK with PV sera caused their detachment from the plates after 20-30 minutes with a complete acantholysis within 12 hours. An early C3 mRNA expression was seen after 30 minutes with a peak level after 1 hour. Blocking studies, using antibodies against human IL-1α and TNF-α in NHuK together with PV-IgG, showed reduction of in vitro induced acantholysis and inhibition of C3 mRNA expression. Conclusions: This study supports the hypothesis that complement C3 is important in PV acantholysis and that complement activation is increased by IL-1α and TNF-α

Direct immunofluorescence diagnosis of pemphigus without biopsy

Background: Direct immunofluorescence (DIF) is a necessary examination tool for the diagnosis of pemphigus. The suction-blister-method splits the skin at the lamina lucida and it is possible with a scalpel to separate the entire epidermis from the dermis. Objective: The study was to determine whether DIF is reliable on epidermal sheets separated using a suction apparatus. Methods: Thirteen patients were selected for this study: (nine with pemphigus vulgaris (PV), one with paraneoplastic pemphigus (PP), and three with pemphigus erythematosus (PE). Frozen epidermal sheets, separated from the dermis with a scalpel, were used as a substrate. Diagnosis with routine fluorescein isothiocyanate (FITC) antibodies was made. Results: In all patients a pericellular deposition of IgG was evident and in eight of these patients a pericellular deposition of C3 was present. In two cases of PE and one of PP, the C3 deposits were also present in the lower part of basal keratinocytes. Conclusion: This diagnostic method without skin biopsy is easy to perform and, together with the histology and clinical aspects, could be a useful tool in the diagnosis of pemphigus. We recommend this method when the patient is allergic to local anaesthetics, the patient easily produces hypertrophic scars, or in follow-up of already biopsied patients

Urokinase plasminogen activator mRNA is induced by IL-1α and TNF-α in in vitro acantholysis

The role of urokinase type plasminogen activator (uPA) has been well documented in the pathogenesis of pemphigus vulgaris (PV). Activation of plasminogen into active serine protease plasmin initiates extracellular proteolysis leading to acantholysis but the mechanisms underlying this process are not clearly understood. We have previously shown that keratinocyte derived cytokines IL-1α and TNF-α are involved in PV-induced acantholysis. In the present study we sought to examine whether keratinocyte-derived IL-1α and TNF-α are correlated with uPA induction in keratinocytes during acantholysis. Normal human keratinocytes were incubated with diluted PV serum. mRNAs for IL-1α, TNF-α and uPA were examined with RT-PCR at various time points and acantholysis was measured. IL-1α, TNF-α and uPA mRNAs were all induced in keratinocytes following PV serum stimulation; IL-1α/TNF-α mRNAs' expression was earlier than the expression of uPA mRNA. To further examine the role of IL-1α, TNF-α and uPA in acantholysis, we performed antibody blocking studies. Anti-IL-la, anti-TNF-a and anti-uPA antibodies suppressed acantholysis by 76%, 80% and 90%, respectively. In addition, anti-IL-1α and anti-TNF-α antibodies inhibited uPA mRNA induction, whereas anti-uPA antibodies did not alter IL-1α/TNF-α mRNAs' expression. Our results confirm the role of uPA in acantholysis and suggest an involvement of IL-1α/TNF-α in uPA induction. © Blackwell Munksgaard, 2003

Direct immunofluorescence diagnosis of pemphigus without biopsy

Background: Direct immunofluorescence (DIF) is a necessary examination tool for the diagnosis of pemphigus. The suction-blister-method splits the skin at the lamina lucida and it is possible with a scalpel to separate the entire epidermis from the dermis. Objective: The study was to determine whether DIF is reliable on epidermal sheets separated using a suction apparatus. Methods: Thirteen patients were selected for this study: (nine with pemphigus vulgaris (PV), one with paraneoplastic pemphigus (PP), and three with pemphigus erythematosus (PE). Frozen epidermal sheets, separated from the dermis with a scalpel, were used as a substrate. Diagnosis with routine fluorescein isothiocyanate (FITC) antibodies was made. Results: In all patients a pericellular deposition of IgG was evident and in eight of these patients a pericellular deposition of C3 was present. In two cases of PE and one of PP, the C3 deposits were also present in the lower part of basal keratinocytes. Conclusion: This diagnostic method without skin biopsy is easy to perform and, together with the histology and clinical aspects, could be a useful tool in the diagnosis of pemphigus. We recommend this method when the patient is allergic to local anaesthetics, the patient easily produces hypertrophic scars, or in follow-up of already biopsied patients

Gelatinases A and B are expressed in late lesions in autoimmune bullous disorders

Gelatinases (or metalloproteinase or collagenases) are involved in remodelling the extracellular matrix in several skin disorders. Previous reports show that the 72 kDa (Gelatinase A), the 92 kDa collagenase (Gelatinase B) and their inhibitors TIMP-2 and TIMP-1 respectively are overexpressed in tumor invasion and metastasis, granuloma annulare, necrobiosis lipoidica diabeticorum and bullous pemphigoid. Usually their natural inhibitors, TIMP-1 and TIMP-2, are inversely related to the production of the 72 kDa and 92 kDa proteins. 8 patients affected by Bullous Pemphigoid (BP) and 8 patients affected by Pemphigus Vulgaris (PV) were biopsized in perilesional areas of young lesions and in lesional areas of old lesions. Materials were snap frozen in liquid nitrogen until use. Antibodies to 72 kDa, 92 kDa, TIMP-1, TIMP-2, CD44, laminin, collagen type I, III, IV, VII were used and evidentiated by the avidin-biotin immunoperoxidase technique. mRNA expression for Gelatinases and their inhibitors were also analyzed by RT-PCR. In all patients we found gelatinases expression only in the late lesions. A different expression was found between the two diseases, the 92 kDa protein and its inhibitor TIMP-1 were positive in both PB and PV whereas the 72 kDa form and its inhibitor TIMP-2 were evident only in PB. By RT-PCR we show that the 72 kDa mRNA was expressed exclusively in the dermis, on the contrary the 92 kDa was present in epidermis and dermis. No signals were detected in the early phase of blistering suggesting a role of gelatinases in re-epithelization but not in blistering where other proteases play a major role. The differential expression of Gelatinases and their inhibitors is probably under a cytokine network control

Gelatinases A and B are expressed in late lesions in autoimmune bullous disorders

Gelatinases (or metalloproteinase or collagenases) are involved in remodelling the extracellular matrix in several skin disorders. Previous reports show that the 72 kDa (Gelatinase A), the 92 kDa collagenase (Gelatinase B) and their inhibitors TIMP-2 and TIMP-1 respectively are overexpressed in tumor invasion and metastasis, granuloma annulare, necrobiosis lipoidica diabeticorum and bullous pemphigoid. Usually their natural inhibitors, TIMP-1 and TIMP-2, are inversely related to the production of the 72 kDa and 92 kDa proteins. 8 patients affected by Bullous Pemphigoid (BP) and 8 patients affected by Pemphigus Vulgaris (PV) were biopsized in perilesional areas of young lesions and in lesional areas of old lesions. Materials were snap frozen in liquid nitrogen until use. Antibodies to 72 kDa, 92 kDa, TIMP-1, TIMP-2, CD44, laminin, collagen type I, III, IV, VII were used and evidentiated by the avidin-biotin immunoperoxidase technique. mRNA expression for Gelatinases and their inhibitors were also analyzed by RT-PCR. In all patients we found gelatinases expression only in the late lesions. A different expression was found between the two diseases, the 92 kDa protein and its inhibitor TIMP-1 were positive in both PB and PV whereas the 72 kDa form and its inhibitor TIMP-2 were evident only in PB. By RT-PCR we show that the 72 kDa mRNA was expressed exclusively in the dermis, on the contrary the 92 kDa was present in epidermis and dermis. No signals were detected in the early phase of blistering suggesting a role of gelatinases in re-epithelization but not in blistering where other proteases play a major role. The differential expression of Gelatinases and their inhibitors is probably under a cytokine network control

A Th2-like cytokine response is involved in Bullous Pemphigoid. The role of IL-4 and IL-5 in the pathogenesis of the disease

Bullous Pemphigoid is an autoimmune bullous disorder characterized by production of IgG against an hemidesmosomal antigen (230 kDa, 180 kDa) responsible for blistering of the skin. In the past several mediators have been implicated in the pathogenesis of the disease such as proteases and collagenases secreted by local inflammatory cells. In order to investigate the role of cytokines in BP, the cytokine pattern was evaluated by an immunohistochemical analysis and by reverse transcriptase polymerase chain reaction procedure in 13 BP patients. Cytokines examined were interleukin (IL)-2, IL-4, IL-5, interferon (IFN)-γ and tumor necrosis factor (TNF)-α. The T cell inflammatory infiltrate was also characterized by monoclonal antibodies showing CD3+, CD4+ T cells with a perivascular and scattered distribution in lesional skin. IL-4 and IL-5 were detected in a similar distribution to the inflammatory infiltrate. IL-4 and IL-5 mRNA levels were also revealed by RT-PCR. Proinflammatory cytokines such as TNF-α, IL-6 and Th1-like cytokines (IL-2 and INF-γ) were not detected neither as proteins nor as mRNA. Since IL-4 and IL-5 are important in eosinophil chemoattraction, maturation and functional activity, the presence of IL-4 and IL-5 in BP suggest that these cytokines could be important in the pathogenesis of the disease

Rethinking the role of tumour necrosis factor-α in ultraviolet (UV) B-induced immunosuppression: Altered immune response in UV-irradiated TNFR1R2 gene-targeted mutant mice

Background: Ultraviolet (UV) B-induced immunosuppression, implicated in the pathogenesis of skin cancers, is postulated to be mediated in part by cis-urocanic acid (cis-UCA) via tumour necrosis factor (TNF)-alpha;. TNF-α produces morphological changes in Langerhans cells indistinguishable from those induced by UVB exposure and antibodies against TNF-α have been demonstrated to inhibit UVB-induced immunosuppression in vivo. Objectives: To clarify further the role of TNF-α in UVB-induced immunosuppression and in cis-UCA immunosuppression. Methods: We performed a contact hypersensitivity (CHS) assay on gene-targeted mutant mice (TNFR1R2-/-) lacking genes for both receptors (p55 and p75) for TNF-α. Mice were either irradiated with UVB or injected intradermally with cis-UCA, sensitized with 2,4-dinitrofluoro-benzene, challenged on the ears and the response was measured. Results: The TNFR1R2-/- mice showed hyporesponsiveness in the CHS response compared with wild-type (P lt; 0.001), confirming the proinflammatory role of TNF-α. However, significant suppression of CHS was seen after irradiation and after cis-UCA injection in both locally (sensitization on irradiated site; P &lt; 0.05) and systemically (sensitization on non-irradiated site; P &lt; 0.05) sensitized wild-type and gene-targeted mice. Conclusions: These results demonstrate that TNF-α signalling is only partially involved in UVB-induced immunosuppression and does not play a major part in the cis-UCA immunosuppression mechanism